Remedies for frequent urination and urinary incontinence

ABSTRACT

The object of this invention is to provide a novel medicinal use for tramadol the safety, among other properties, of which has already been established. This invention is directed to a therapeutic or prophylactic composition for urinary frequency and a therapeutic or prophylactic composition for urinary incontinence, both comprising tramadol or a salt thereof. The preferable salt of tramadol includes tramadol hydrochloride.

TECHNICAL FIELD

This invention relates to a therapeutic or prophylactic composition forurinary frequency or a therapeutic or prophylactic composition forurinary incontinence, which comprises tramadol or a salt thereof as anactive ingredient.

BACKGROUND ART

Tramadol is an opioid non-narcotic analgesic drug having the chemicalname oftrans-(±)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol andhas heretofore been used broadly in the form of hydrochloride for themanagement of intense to moderate pain.

Urinary incontinence is a disease generally considered to occur when theintravesical pressure involuntarily exceeds the urethral closurepressure and is suspected to involve, as an etiologic factor, anincrease in intravesical pressure (which chiefly causes urge urinaryincontinence or urinary frequency) or a decrease in urethral closurepressure (which chiefly causes stress urinary incontinence).

The current pharmacotherapeutic regimen in urinary frequency or urinaryincontinence includes the drugs adapted to lower intravesical pressure,i.e. decrease the contractility of the detrusor muscle, such asanticholinergic drugs (e.g. oxybutynin, propiverine), tricyclicantidepressants (e.g. imipramine), smooth muscle direct relaxants (e.g.flavoxate), etc., and the drugs adapted to increase the urethral closurepressure, i.e. increase the resistance of bladder neck or the urethra,such as α-adrenergic agonists (e.g. ephedrine), β-adrenergic agonists(e.g. clenbuterol) and female hormones (e.g. estradiol). Opioidanalgesics are not included in this therapeutic regimen.

Up to the present, there is no report indicating that any drug belongingto the established and clinically accepted class of opioid analgesics,represented by morphine, is ever effective in the treatment of urinaryfrequency or urinary incontinence. In addition, as to tramadol, it isnot known at all that, as a main efficacy, this drug is effective in thetherapy of urinary frequency or urinary incontinence.

DISCLOSURE OF INVENTION

The object of this invention is to provide a novel medicinal use fortramadol the safety, among other properties, of which has already beenestablished.

The inventors of this invention did intensive investigations and foundthat tramadol is effective in the treatment of urinary frequency orurinary incontinence as a main efficacy. This invention has come forthfrom the above finding.

This invention is directed to a therapeutic or prophylactic compositionfor urinary frequency and a therapeutic or prophylactic composition forurinary incontinence, both comprising tramadol or a salt thereof[hereinafter referred to as the drug of the invention] as an activeingredient [both compositions are collectively referred to herein as thepharmaceutical composition of this invention]. This invention may bedefined also as the use of the drug of the invention for the manufactureof said pharmaceutical composition for the therapy or prophylaxis ofurinary frequency or said pharmaceutical composition for the therapy orprophylaxis of urinary incontinence, which contain the drug of theinvention as an active ingredient. Furthermore, this invention may alsobe defined as a method for the therapy or prophylaxis of urinaryfrequency or urinary incontinence which comprises using the drug of theinvention.

The salt of tramadol is not particularly restricted as far as it is apharmaceutically acceptable acid addition salt, thus including saltswith inorganic acid, e.g. hydrochloride, sulfate, nitrate, phosphate,hydrofluoride, hydrobromide, etc. and salts with organic acids such asacetate, tartrate, lactate, citrate, fumarate, maleate, succinate,methanesulfonate, benzenesulfonate, toluenesulfonate,naphthalenesulfonate, camphorsulfonate and so forth. Particularlypreferred is tramadol hydrochloride which is in broad use as ananalgesic.

BEST MODE FOR CARRYING OUT THE INVENTION

The pharmaceutical composition of the invention or the drug of theinvention can be used in the therapy or prophylaxis of urinary frequencyor urinary incontinence (mainly urge urinary incontinence and stressurinary incontinence) in animals inclusive of humans.

The dosage of the drug of the invention varies with the patient's age,body weight and other background, the route of administration, thenature and stage of disease, among other factors, but the usual dailydosage for an adult human may judiciously fall within the range of0.01-400 mg, preferably 0.1-200 mg, more preferably 1-100 mg. Reduceddoses may be sufficient in some cases, while some escalation of saiddosage may be needed in other cases. The drug of the invention can beused in a dose range not over the usual dose range for use as ananalgesic. Moreover, the pharmaceutical composition (drug) of theinvention may be administered in 2-5 divided doses a day.

The pharmaceutical composition of the invention may comprise the drug ofthe invention as it is or contain the same as formulated, within a rangeof 0.01%-99.5%, more preferably 0.5%-90%, in a pharmaceuticallyacceptable, nontoxic and inert carrier.

As the carrier mentioned above, one or more of solid, semisolid orliquid diluents, fillers and/or other auxiliary formulating additivescan be used. The pharmaceutical composition of the invention ispreferably administered in unit dosage forms. Thus, the pharmaceuticalcomposition of the invention may be provided in any of oral dosageforms, e.g. bulk powder, capsules, tablets, sugar-coated tablets,granules, powders, suspension, solution, syrup, elixir, drops,sublingual tablets, etc., and non-oral dosage forms, e.g. injections,suppositories, etc., regardless of whether it is in a solid form or in aliquid form but each containing a unit dose. It may also be asustained-release dosage form. Particularly preferred is an oral dosageform, such as tablets.

The bulk powder can be prepared by comminuting the drug of the inventionto a suitable particle size. The powder can be manufactured bycomminuting the drug of the invention to a suitable particle size andblending it with a similarly comminuted pharmaceutical carrier such asan edible carbohydrate, e.g. starch and mannitol, or the like.Optionally, a corrigent, a preservative, a dispersant, a coloring agent,a flavoring agent and/or other additives may also be formulated.

The capsules can be manufactured by filling the bulk powder or powderprepared by said comminuting technology or the granules prepared by themethod to be described below for tablets into capsule shells, e.g.gelatin capsule shells. Preceding this filling operation, the abovepowdery or granular preparation may be supplemented and blended with alubricant or fluidizing agent such as colloidal silica, talc, magnesiumstearate, calcium stearate and solid polyethylene glycol. The efficacyof the drug after intake of the capsules is enhanced by addition of adisintegrator or solubilizing agent such as carboxymethyl-cellulose,carboxymethylcellulose calcium, low-substitution-degreehydroxypropylcellulose, croscarmellose sodium, carboxymethylstarchsodium, calcium carbonate and sodium carbonate. Furthermore, a finelydivided powder of the drug of the invention may be suspended anddispersed in vegetable oil, polyethylene glycol, glycerin or asurfactant and the dispersion be packaged with gelatin sheet to providesoft capsules.

The tablets can be manufactured by adding an excipient, granulating orslugging the resulting mixed powder, adding a disintegrator or alubricant and compressing the mixture. The mixed powder can be preparedby blending a suitably comminuted powder of the drug with said diluentor a base, optionally with the addition of a binder (e.g.carboxymethylcellulose sodium, methylcellulose,hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinylalcohol, etc.), a dissolution retardant (e.g. paraffin), a reabsorptionagent (e.g. quaternary salts) and an adsorbent (e.g. bentonite, kaolin,etc.). The mixed powder can be first wetted with a binder such as asyrup, a starch paste, gum arabic, a cellulose solution or a polymersolution, stirred to mix, dried and pulverized to provide granules.Instead of granulating, the powder may be compression-molded with atablet machine and the resulting slugs, i.e. an incomplete product, becrushed to provide granules. The granules thus obtained can be protectedagainst inter-adhesion or caking by adding a lubricant such as stearicacid, its salt, talc, mineral oil or the like. The thus-lubricatedmixture can then be compressed into tablets. The bare tablets soobtained can be film-coated or sugar-coated. The drug of the inventionmay optionally be directly compressed into tables after admixing it witha free-flowing inert carrier, omitting said granulation or sluggingoperation. A transparent or translucent protective coat such as ahermetic shellac coat and a wax glaze coat may also be applied.

Other products for oral administration, such as a solution, a syrup, atroche, an elixir, etc., can also be provided in unit dose forms eachcontaining a calculated amount of the drug of the invention. The syrupcan be manufactured by dissolving the drug of the invention in asuitable flavored aqueous medium and the elixir can be manufacturedusing a nontoxic alcoholic vehicle. The suspension can be manufacturedby dispersing the drug of the invention in a nontoxic vehicle. Wherenecessary, a solubilizer and/or an emulsifier (e.g. ethoxylatedisostearyl alcohols, polyoxyethylene-sorbitol esters, etc.), apreservative and a flavoring agent or corrident (e.g. peppermint oil,saccharin) can also be added.

Where necessary, the unit dose formulation for oral administration maybe microencapsulated. This formulation may be coated with or embedded ina polymer, wax or other matrix for prolonging the drug action orensuring a sustained release of the drug.

The composition for non-oral administration can be provided in liquiddosage forms for subcutaneous, intramuscular or intravenousadministration, such as a solution or a suspension. Those dosage formscan be manufactured by suspending or dissolving a calculated amount ofthe drug of the invention in a nontoxic liquid vehicle for injection,such as an aqueous or oily medium, and sterilizing the resultingsolution or suspension. To render such an injection isotonic, a nontoxicsalt or its solution can be added. Moreover, a stabilizer, apreservative, an emulsifier, etc. can also be added.

The suppositories can be manufactured by dissolving or suspending thecompound in a water-soluble or insoluble low-melting solid base such aspolyethylene glycol, cacao butter, semi-synthetic oil (e.g. Witepsol® ),a higher ester (e.g. myristyl palmitate) or a mixture thereof.

EXAMPLES

The following test example illustrates the usefulness of the drug of theinvention in the treatment of urinary frequency or urinary incontinenceand describes this invention in further detail.

Test Example

Cystometry test: Effect on the lower urinary tract function

Female Sprague-Dawley rats weighing 180-230 g (SLC Japan) wererespectively immobilized in supine position under urethane anesthesia(900 mg/kg s.c.). After a midline incision was made in the lowerabdominal region, the ureters were ligated and cut on the bladder side.The urine from the kidneys was withdrawn from the body through cannulaeinserted into the ureters. A T-tube was connected to the free end of acannula inserted into the bladder apex. Then, warmed saline was infusedfrom one branch of the T-tube into the urinary bladder at a rate of 2.8ml/hr until the reflex micturition had occurred and the change inintravesical pressure during the intervening time was recorded from theother branch. In this cystometry test, the bladder capacity (thecapacity of the urinary bladder at reflex micturition) and the maximumbladder contraction pressure (the maximum intravesical pressure atvoiding) were confirmed to occur in a steady manner twice consecutively,after which the test drug (tramadol hydrochloride, supplied byGrunenthal GmbH) was administered intraduodenally. After 30, 60, 120 and180 minutes, cystometry was performed to examine changes in bladdercapacity and maximum bladder contraction pressure. During the aboveexperiment, the animal's body temperature was kept constant using awarming device.

The results of the above experiment were expressed as the mean ±S.E ofbladder capacity or maximum bladder contraction pressure, andstatistical analysis was made between the control and drug-treatedgroups by one-way analysis of variance, followed by the Dunnett multiplecomparison. The level of significance was p<0.05. The test drug(tramadol hydrochloride) was dissolved in physiological saline atconcentrations appropriate for an injection volume of 1 ml/kg. Thecontrol group received the same volume of saline via the duodenum.

The effect on bladder capacity is shown in Table 1 and effect on maximumbladder contraction pressure is shown in Table 2.

                                      TABLE 1                                     __________________________________________________________________________    (Bladder capacity)                                                                      Bladder capacity (ml)                                                   Dose  Before                                                                              After   After   After After                                   Drug                                                                              (mg/kg)                                                                           N dosing                                                                              30 min  60 min  120 min                                                                             180 min                                 __________________________________________________________________________    Control                                                                           --  5 0.39 ± 0.02                                                                      0.39 ± 0.02                                                                        0.39 ± 0.03                                                                        0.39 ± 0.03                                                                      0.40 ± 0.03                          Test                                                                              0.3 5 0.37 ± 0.03                                                                      0.40 ± 0.05                                                                        0.34 ± 0.04                                                                        0.35 ± 0.03                                                                      0.38 ± 0.03                          drug                                                                              1   5 0.36 ± 0.02                                                                      0.49 ± 0.05                                                                        0.49 ± 0.08                                                                        0.44 ± 0.06                                                                      0.42 ± 0.03                              3   5 0.36 ± 0.01                                                                       0.62 ± 0.04**                                                                      0.61 ± 0.04**                                                                     0.53 ± 0.07                                                                      0.50 ± 0.07                          __________________________________________________________________________     N represents the number of animals.                                           Each bladder capacity value represents the mean ± standard error.          **: p < 0.01 (versus control group)                                      

                                      TABLE 2                                     __________________________________________________________________________    (Maximum bladder contraction pressure)                                                  Maximum contraction pressure (mmHg)                                     Dose  Before                                                                              After After After After                                       Drug                                                                              (mg/kg)                                                                           N dosing                                                                              30 min                                                                              60 min                                                                              120 min                                                                             180 min                                     __________________________________________________________________________    Control                                                                           --  5 20.86 ± 1.26                                                                     19.95 ± 1.12                                                                     20.63 ± 0.93                                                                     20.64 ± 0.58                                                                     21.41 ± 0.63                             Test                                                                              0.3 5 21.32 ± 2.04                                                                     22.65 ± 2.07                                                                     21.67 ± 1.31                                                                     21.90 ± 1.72                                                                     20.63 ± 1.74                             drug                                                                              1   5 22.52 ± 1.25                                                                     22.81 ± 1.93                                                                     21.94 ± 1.23                                                                     22.02 ± 1.66                                                                     20.00 ± 1.58                                 3   5 21.96 ± 1.18                                                                     23.96 ± 2.34                                                                     22.70 ± 2.23                                                                     21.30 ± 2.48                                                                     21.27 ± 3.22                             __________________________________________________________________________     N represents the number of animals.                                           Each maximum bladder contraction pressure value represents the mean ±      standard error.                                                          

It is indicated from Table 1 that the test drug tramadol hydrochloridecaused a tendency toward increased bladder capacity at the dose level of1 mg/kg and a significant increase in bladder capacity at 30 and 60minutes after dosing at 3 mg/kg. From Table 2, it can be seen that thetest drug tramadol hydrochloride had no significant difference from thecontrol in terms of the absence of influencing the maximum bladdercontraction pressure, thus suggesting that the drug has only a low riskfor increasing residual urine.

EFFECT OF THE INVENTION

As mentioned above, it is apparent that the drug of the invention isavailable not only for an analgesic drug, but also for the treatment ofurinary frequency or urinary incontinence.

What is claimed is:
 1. A method of treating or prophylaxis of urinaryfrequency in a subject comprising administering to the subject atherapeutic or prophylactic composition comprising tramadol or a saltthereof.
 2. A method of treating or prophylaxis of urinary incontinencein a subject comprising administering to the subject a therapeutic orprophylactic composition comprising tramadol or a salt thereof.
 3. Themethod of claim 1, wherein the therapeutic or prophylactic compositioncomprises tramadol hydrochloride.
 4. The method of claim 2, wherein thetherapeutic or prophylactic composition comprises tramadolhydrochloride.